Project Summary Possession of the ?4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late onset Alzheimer?s disease (AD), although the direct cause remains a source of debate. While research suggests that APOE4 expression can increase the phosphorylation, aggregation and neurotoxicity of tau in the brain, it has yet to be investigated whether APOE4 can accelerate the propagation of tau through the brain, a process that is highly correlated with the cognitive decline of AD patients. Preliminary work that I have recently published shows that APOE4 expression in mice leads to an increase in brain activity in the entorhinal cortex (EC), one of the first brain regions affected by tau pathology during AD. This finding, along with additional data showing that neuronal hyperactivity can increase tau release and propagation, suggests that this APOE4-associated hyperactivity that I have observed may accelerate the propagation of tauopathy out of the EC and into neighboring brain regions. To test this hypothesis, I will utilize a novel mouse line in which human APOE3 and APOE4 mice are crossed with EC-Tau mice, which predominantly expresses tau in the EC. Preliminary data on these APOE/EC-Tau mice also suggests that this mouse model may be a useful tool for studying the ability of APOE4 to accelerate tauopathy-induced neurodegeneration in an AD-relevant brain region. Through a series of studies on these APOE/EC-Tau mice, I will elucidate the ability of APOE4 to both accelerate tauopathy propagation through the brain, as well as to increase tauopathy-induced neurodegeneration in the EC. As both APOE4 and tau significantly impact AD, elucidating the link between them would represent a major breakthrough in the field and has the potential to lead to novel therapeutic strategies for preventing or treating AD, especially among APOE4 carriers.